Method and apparatus for nitric oxide generation

ABSTRACT

Inhalation of low levels of nitric oxide can rapidly and safely decrease pulmonary hypertension in mammals. Precise delivery of nitric oxide at therapeutic levels of 20 to 100 ppm and inhibition of reaction of nitric oxide with oxygen to form toxic impurities such as nitrogen dioxide can provide effective inhalation therapy for pulmonary hypertension.

CLAIM OF PRIORITY

[0001] This application claims the benefit of U.S. Application No.60/316,964 filed on Sep. 5, 2001, which is incorporated by reference inits entirety.

CROSS REFERENCE TO RELATED APPLICATIONS

[0002] The present application is related to co-pending application(Attorney Docket No. 10897-022001) entitled “Controlled Generation ofNitric Oxide,” filed concurrently herewith, and co-pending application(Attorney Docket No. 10897-023001) entitled “Nitric Oxide DeliverySystem,” also filed concurrently herewith, each of which is incorporatedby reference in its entirety.

TECHNICAL FIELD

[0003] This invention relates to an apparatus and a method forcontrollably generating nitric oxide.

BACKGROUND

[0004] Nitric oxide plays an important role in the regulation ofbiochemical pathways in living organisms. The inhalation of low levels(20 to 100 ppm) of nitric oxide has been shown to have a majortherapeutic value in treatment of a diverse range of disorders rangingfrom reversible and irreversible pulmonary hypertension to treatment ofneonates exhibiting hypoxemic respiratory failure and persistentpulmonary hypertension. Conventional medical uses of nitric oxide gascan involve dilution of a nitric oxide gas stream with gases immediatelybefore administration of the nitric oxide gas to a mammal. Precisedelivery of nitric oxide at therapeutic levels of 20 to 100 ppm andinhibition of reaction of nitric oxide with oxygen to form toxicimpurities such as nitrogen dioxide gas is needed for effectiveinhalation therapy.

SUMMARY

[0005] Nitric oxide, also known as nitrosyl radical, is a free radicalthat is an important signaling molecule in pulmonary vessels. Nitricoxide can moderate pulmonary hypertension caused by elevation of thepulmonary arterial pressure. Inhaling low concentrations of nitricoxide, for example, in the range of 20-100 ppm can rapidly and safelydecrease pulmonary hypertension in a mammal by vasodilation of pulmonaryvessels.

[0006] Some disorders or physiological conditions can be mediated byinhalation of nitric oxide. The use of low concentrations of inhalednitric oxide can prevent, reverse, or limit the progression of disorderswhich can include, but are not limited to, acute pulmonaryvasoconstriction, traumatic injury, aspiration or inhalation injury, fatembolism in the lung, acidosis, inflammation of the lung, adultrespiratory distress syndrome, acute pulmonary edema, acute mountainsickness, post cardiac surgery acute pulmonary hypertension, persistentpulmonary hypertension of a newborn, perinatal aspiration syndrome,haline membrane disease, acute pulmonary thromboembolism,heparin-protamine reactions, sepsis, asthma and status asthinaticus orhypoxia. Nitric oxide can also be used to treat chronic pulmonaryhypertension, bronchopulmonary dysplasia, chronic pulmonarythromboembolism and idiopathic or primary pulmonary hypertension orchronic hypoxia. Advantageously, nitric oxide can be generated anddelivered in the absence of harmful side products, such as nitrogendioxide. The nitric oxide can be generated at a concentration suitablefor delivery to a mammal in need of treatment.

[0007] In one aspect, an apparatus for delivering a therapeutic gasincluding nitric oxide includes a receptacle including a therapeutic gasoutlet and a non-electrolytic nitric oxide precursor receiver and atransport gas inlet fluidly communicating from a source of a transportgas to the therapeutic gas outlet through the non-electrolytic nitricoxide precursor receiver. The therapeutic gas delivery system can befluidly connectable to the therapeutic gas outlet. The therapeutic gasdelivery system can include a gas purifier which can be, for example, afilter. The therapeutic gas delivery system can include a mask fluidlyconnectable to the therapeutic gas outlet that can be connectable to amammal.

[0008] In another aspect, a method of delivering nitric oxide to amammal includes non-electrolytically generating a therapeutic gas from anitric oxide precursor, wherein the therapeutic gas includes nitricoxide and is substantially devoid of nitrogen dioxide and transportingthe therapeutic gas to a mammal. Non-electrolytically generating thetherapeutic gas can include contacting the nitric oxide precursor with abuffer solution to form a mixture. The buffer solution can be a pHbuffer combination. The pH buffer combination can include aceticacid/acetate, hydrochloric acid/chloride, hydrochloric acid/citrate,citric acid-phosphate, phosphoric acid/phosphate or citric acid/citrate.The pH of the mixture can be in the range of 4 to 7 or 6.5 to 6.9. Thenitric oxide precursor can be a nitrite salt. The nitrite salt can be,for example, sodium nitrite. The transport gas can be, for example,swept over the mixture. The therapeutic gas can deliver, for example, 20to 60 ppm nitric oxide to the mammal. The transport gas can be oxygen,ambient air or a mixture of air and oxygen. The nitric oxide can bereleased from the precursor for over at least an hour. The therapeuticgas can be substantially devoid of nitrogen dioxide.

[0009] In another aspect, a kit includes a nitric oxide precursor andinstructional material describing a method of generating a therapeuticgas and transporting the therapeutic gas, the therapeutic gas comprisingnitric oxide and being substantially devoid of nitrogen dioxide. Thenitric oxide precursor can be a nitrite salt. The nitrite salt can be,for example, sodium nitrite. The nitric oxide can be released from theprecursor for over at least an hour. Other features or advantages willbe apparent from the following detailed description of severalembodiments, and also from the appended claims.

DESCRIPTION OF DRAWING

[0010]FIG. 1 is a drawing depicting a schematic view of a nitric oxidegeneration and delivery system.

DETAILED DESCRIPTION

[0011] Various nitric oxide precursors can be used in a nitric oxidedelivery system. Nitric oxide precursors can include anitrogen-containing compound with a structure X-nitric oxide, when X isan organic residue or a precursor salt. For example, the nitric oxideprecursor can include an alkali metal nitrite, an alkaline earth metalnitrite, a transition metal nitrite or an ammonium nitrite, for example,potassium nitrite, sodium nitrite, rubidium nitrite, strontium nitrite,barium nitrite, calcium nitrite, copper nitrite, zinc nitrite, ormixtures thereof. The nitric oxide precursor can includenitrogen-containing acids, such as nitric acid. Physical characteristicsof the nitric oxide precursor, such as the dissolution rate, can be usedto control delivery of nitric oxide.

[0012] The nitric oxide precursor can be dissolved in a solution inwhich the precursor can dissociate to form anions, including nitriteanions, and cations. The solution can include a buffer solution. Abuffer solution can include a pH buffer combination which is a solutioncontaining either a weak acid or a weak base at a concentration thatrenders the solution resistant to change in pH. The buffer solutionprovides a source of hydrogen cations, which can combine with thenitrite anions to form nitrous acid (HNO₂). Nitrous acid can decomposeinto several products in water. One of these products is nitric oxide.The reactions are summarized below in equations (I), (II) and (III):

NaNO₂⇄Na⁺+NO₂ ⁻  (I)

NO₂ ⁻+H⁺⇄HNO₂  (II)

3HNO₂⇄H₂O+H⁺+NO₃ ⁻+2NO  (III)

[0013] The nitric oxide precursor can include sodium nitrite, whichdissociates into sodium cations and nitrite anions, as shown in equation(I). The nitrite anions in the buffer solution can form nitrous acid asshown in equation (II), which can decompose into water, nitrate andhydrogen ions and two molecules of gaseous nitric oxide, as shown inequation (III).

[0014] The generated nitric oxide gas formed by the above reactions hasa low solubility in the pH buffer combination (e.g., 0.00983 g nitricoxide per liter at 0° C.; 4.6 mL/100 mL at 20° C. in water (Merck Index,10th Edition, 1983)). The relatively insoluble nitric oxide can beremoved from the solution by a transport gas stream to form atherapeutic gas. The transport gas can be 100% oxygen, a mixture of airand oxygen or ambient air. The transport gas stream can be bubbled,otherwise distributed through the solution or swept over the headspaceof the solution. Other byproducts such as, for example, nitrous acid andnitrogen dioxide, can be volatile and can be carried with the transportgas stream along with nitric oxide formed in the reaction.

[0015] When delivering nitric oxide for therapeutic use to a mammal, itcan be important to avoid delivery of nitrogen dioxide to the mammal.Nitrogen dioxide can be formed by the oxidation of nitric oxide withoxygen. The rate of formation of nitrogen dioxide is proportional to thesquare power of the nitric oxide concentration and the first power ofthe oxygen concentration. Reducing the nitric oxide concentration by afactor of ten reduces the nitrogen dioxide concentration by a factor ofone hundred. Thus, by limiting the nitric oxide concentration in atherapeutic gas, the therapeutic gas can be substantially devoid ofnitrogen dioxide. For example, when nitric oxide concentration in thetransport gas is below 100 ppm, the resulting therapeutic gas generatedfrom the nitric oxide precursor in a solution is substantially devoid ofnitrogen dioxide.

[0016] In certain circumstances, the concentration of nitric oxidegenerated in the therapeutic gas is controlled, for example, by theconcentration of nitric oxide precursor provided to the solution, theconcentration of hydrogen cations in the solution, and thecharacteristics of the pH buffer combination. Other factors that canaffect the nitric oxide concentration in the therapeutic gas caninclude, for example, physical form of the nitric oxide precursor,presence of a reduction-oxidation reaction in an optional gas purifier,and rate of flow of the transport gas through the solution.

[0017] The concentrations of hydrogen cations and the nitric oxideprecursor can control the rate of generation of nitric oxide. Since theconcentration of nitric oxide is low, about 20 to 100 ppm, reactionconditions, that increase the concentration of nitric oxide precursorand decrease the concentration of hydrogen ions lead to astoichiometrically inefficient reaction. Decreasing the concentration ofhydrogen ions, for example, by using a weak acid, shifts the equilibriumin equation (II) toward the nitrite anions. A reservoir of nitrite ionscan be created such that the nitrous acid concentration is maintained ata relatively constant level.

[0018] Referring to FIG. 1, a nitric oxide delivery system 100 forproducing a therapeutic gas including nitric oxide includes a transportgas pump 110, a restrictor valve 115, a tube 120, and a receptacle 130.The pump can be a diaphragm pump. The receptacle 130 includes anon-electrolytic nitric oxide precursor receiver 135. Thenon-electrolytic nitric oxide precursor receiver is a receiver that doesnot require application of voltage for the nitric-oxide generatingreaction to proceed. The non-electrolytic nitric oxide precursorreceiver includes a transport gas inlet 170 and a therapeutic gas outlet145. The therapeutic gas outlet 145 is connectable to a gas deliverysystem, which includes a tube 140, an optional gas purifier 150, a tube160, and a mask 180. The mask 180 is connectable to a mammal. Thetransport gas inlet 170 includes a gas distributor 175. The gasdistributor 175 distributes the transport gas in the receiver 135. Thegas distributor 175 can be a mechanical agitator, which can include, forexample, a stirrer, a vibrator, a sparger and a bubbler to preventsupersaturation of nitric oxide in the receiver 135. The a transport gaspump 110 controls flow rate of a transport gas through the receiver. Forexample, the flow rate can be from 1 to 10 liters per minute, 2-8 litersper minute or 2 to 5 liters per minute. The flow rate of the transportgas can be in the range of 1 to 20 liters per minute. The transport gascan be 100% oxygen, a mixture of air and oxygen, or ambient air. Therate of flow of transport gas in the reaction vessel can affect thegeneration of nitric oxide. Mechanical agitation using, for example,stirring, vibration, or bubbling the transport gas through the solution,sweeping the transport gas over the solution or other methods ofagitation enhances the transport of nitric oxide in the therapeutic gas.

[0019] In a general process for delivering nitric oxide, the a transportgas pump 110 conveys a stream of transport gas at a specific flow rate,into and through the tube 120 and into and through the non-electrolyticnitric oxide precursor receiver 135, which contains the nitric oxideprecursor and buffer solution. The non-electrolytic nitric oxideprecursor receiver 135 can be, for example, filled to half the capacitywith the nitric oxide precursor and the buffer solution, for example, apH buffer combination. The pH buffer combination can be used to controlthe pH of the solution to very close to pH 7 to maintain a concentrationof hydrogen ions suitable to control nitric oxide production from thesolution. Suitable pH buffers include, for example, combinations ofacetic acid and acetate salt (acetic acid/acetate), combinations ofhydrochloric acid and chloride salt, combinations of hydrochloric acidand citrate salt (hydrochloric acid/citrate), combinations of citricacid and phosphate salt (citric acid-phosphate), combinations ofphosphoric acid and phosphate salt (phosphoric acid/phosphate) andcombinations of citric acid and citrate salt (citric acid/citrate). A pHwithin the range of 4.5-7.0, or the range of 6.5-6.9, can be maintainedin the solution using the pH buffer combination.

[0020] Nitric oxide is generated in the nitric oxide precursor receiver135. The stream of transport gas carries the generated nitric oxide asthe therapeutic gas into and through tube 140 into (optionally) a gaspurifier 150. If necessary, the therapeutic gas can pass into andthrough the optional gas purifier 150 which can remove any residualimpurities such as nitrogen dioxide and nitrous acid, if present. Thetherapeutic gas including the nitric oxide is transported in thetransport gas into and through tube 160 to mask 180 to the mammal. Themask 180 can include any device or implement that is used to provide thenitric oxide stream to the mammal and is typically selected by thephysician based on the mammal need and condition. For example, the mask180 can be in the form of a tight-fitting or a loose fitting mask, anintubation tube, a nasal delivery tube, or a tube that generally directsthe nitric oxide gas in the region around the mammal's mouth and/ornose.

[0021] In certain circumstances, the therapeutic gas can be passedthrough a nitric oxide releasing solution. A nitrite releasing saltassists in the generation of nitric oxide from the nitric oxideprecursor. For example, a second salt, such as a nitric oxide-releasingreactant, can be added to the solution. A nitric oxide-releasingreactant, for example, an iodide salt or ferrous salt, assists theproduction of nitric oxide as shown below:

2NO₂ ⁻+2I⁻+4H⁺→I₂+2H₂O+2NO

or

2NO₂ ⁻+2Fe⁺²+6e⁻→2Fe⁺³+2H₂O+2NO

[0022] For example, the nitric oxide-releasing reactant can be 1 molarferrous sulfate solution or 10% wt/wt aqueous solution of sodium iodide.The nitrite releasing salt can include salts of Groups I, II, III, IV,V, VI and VII of the periodic table. For example, the nitrite releasingsalt can include a ferrous salt.

[0023] In certain circumstances, the therapeutic gas can be passedthrough an optional therapeutic gas purifier 150. When the therapeuticgas stream contacts the optional therapeutic gas purifier, residualimpurities, such as nitrous acid and nitrogen dioxide, are removed fromthe therapeutic gas stream. The optional gas purifier can include afilter, which can be, for example, a semi-permeable membrane or barrier,a scrubbing solution, a reduction-oxidation solution, or a pyrolizer.The semi-permeable membrane is a barrier which allows the nitric oxideto pass and retains the impurities. The scrubbing solution is a solutionthat removes impurities by neutralizing them, for example, a solution of10% sodium bicarbonate, a 1M ferrous salt solution or an acidified 1Mferrous sulfate solution. A series of aqueous reservoirs can be used tocompletely decompose the nitrous acid and dissolve any nitric acid ornitrogen dioxide impurities. The reduction-oxidation solution contains areduction-oxidation agent, which converts impurities completely intonitric oxide. The reduction-oxidation agent can include a ferrous salt.The pyrolizer is a chamber or other component which decomposes theimpurities such as nitrous acid and nitrogen dioxide by irradiation orheating. A catalyst, for example, platinum, nickel or silver, can beused to decrease the pyrolysis temperature. For example, the impuritiessuch as nitrous acid and nitrogen dioxide can be passed through a 12inch long silver tube, ⅛ inch in diameter, heated at 800° C. at a flowrate of 1 L/minute. The removal of impurities can be enhanced by using aconvoluted or a long path for conducting the therapeutic gas streamthrough the filter. Additionally, the surface-to-volume ratio of thebubbles can be increased for effective filtration of impurities. Forexample, a gas sparger can be used to make smaller bubbles.Alternatively, filter media can also be coated onto a filter or walls ofa tube, which can produce a dry therapeutic gas stream upon filtration.

[0024] A detector can be included in the therapeutic gas delivery systemto detect the concentration of nitric oxide in the therapeutic gasstream. The detector can also detect the concentration of nitrogendioxide in the therapeutic gas, if necessary, and may provide a warningif the nitric oxide concentration is outside a predetermined range or ifthe concentration of nitrogen dioxide is above a threshold value.Examples of monitoring techniques include chemiluminescence andelectrochemical techniques, and are discussed in, for example, inFrancoe et al., “Inhaled nitric oxide: Technical Aspects ofAdministration and Monitoring,” Critical Care Medicine, 24(4): 782-796(1998) which is incorporated by reference in its entirety. The presenceof nitric oxide can be detected by for example, a modified version of aThermo-Electron chemiluminescence (CL) detector.

[0025] A kit includes the nitric oxide precursor and instructionalmaterial describing a method of generating the therapeutic gas andtransporting the therapeutic gas in the transport gas. The therapeuticgas including nitric oxide is substantially devoid of impurities such asnitrogen dioxide.

[0026] A therapeutic gas can contain at least 1 ppm of nitric oxide. Thetherapeutic gas can include less than 100 ppm of nitric oxide. Forexample, the nitric oxide concentration in the therapeutic gas can befrom 20 to 100 ppm. The nitric oxide can be released from the precursorover a period of time ranging from 1 minute to 7 days, 2 days to 3 days,or two hours to twenty four hours.

[0027] Oxidation-reduction reactions can assist in the production ofnitric oxide. For example, a second salt, such as a nitricoxide-releasing reactant, can be added to the solution. A nitricoxide-releasing reactant, for example, an iodide salt or ferrous salt,assists the production of nitric oxide as shown below:

2NO₂ ⁻+2I⁻+4H⁺→I₂+2H₂O+2NO

or

2NO₂ ⁻+2Fe⁺²+6e⁻→2Fe⁺³+2H₂O+2NO

[0028] For example, the nitric oxide-releasing reactant can be a 1 molarferrous sulfate solution or a 10 wt % aqueous solution of sodium iodide.The following examples describe nitric oxide generation.

EXAMPLE 1

[0029] Using an apparatus depicted in FIG. 1, a pH buffer combination(100 mL) was prepared which was 1M acetic acid and 1M acetate with a pHof 4.9 and added to a non-electrolytic nitric oxide precursor receiver.Twenty grams of sodium nitrite (approximately 2M) was added to thereceiver and the mixture was stirred at room temperature. A transportgas pump equipped with a restrictor valve was used to establish a flowrate of 2 liters per minute of ambient air at 20° C.. The transport gasswept the headspace of the nitric oxide receiver to generate thetherapeutic gas. The output of nitric oxide generated was 50 ppm in thetherapeutic gas, which remained constant at 50 ppm+/−20 ppm for fivehours.

EXAMPLE 2

[0030] Using an apparatus depicted in FIG. 1, a pH buffer combination(100 mL) was prepared which was 3M acetic acid and 3M acetate with a pHof 4.9 was added to a non-electrolytic nitric oxide receiver. Twentygrams of sodium nitrite (approximately 2M) was added to the receiver andthe reaction was stirred at room temperature. A transport gas pumpequipped with a restrictor valve was used to establish a flow rate of 2liters per minute of ambient air at 20° C. The transport gas swept theheadspace of the nitric oxide reciever to generate the therapeutic gas.The output of nitric oxide generated was 50 ppm in the therapeutic gas,which remained constant at 50 ppm+/−20 ppm for nine hours.

EXAMPLE 3

[0031] Using an apparatus depicted in FIG. 1, a solution was prepared ina non-electrolytic nitric oxide precursor receiver, by dissolving 28grams of sodium hydrogen phosphate dibasic (Na₂HPO₄) in 100 mL of water.Sodium nitrite (15 g) was added to the solution, followed by addition of40 g of sodium hydrogen phosphate monobasic (NaH₂PO₄) until the solutionbecame clear. The total volume of the solution was adjusted to 150 mL.The pH of the solution was approximately 4. In the optional gaspurifier, a 0.1 mole of ferrous sulfate (FeSO₄) was dissolved in 100 mLof water. A transport gas pump equipped with a restrictor valve was usedto establish a flow rate of 2 liters per minute of ambient air at 20° C.The transport gas swept the headspace of the nitric oxide receiver togenerate the therapeutic gas. The output of nitric oxide generated inthe therapeutic gas was 60 ppm in the therapeutic gas, for a period ofseven days.

EXAMPLE 4

[0032] Using an apparatus depicted in FIG. 1, a pH buffer combinationand nitric oxide precursor mixture was prepared by adding 0.1 molesodium phosphate monobasic, 0.1 mole sodium phosphate dibasic and 20 gof sodium nitrite to 100 mL of water. The pH of the solution wasapproximately 5.6. A gas flow controller equipped with a restrictorvalve was used to establish a flow rate of 2 liters per minute ofambient air at 20° C. The transport gas was swept over the headspace ofthe nitric oxide precursor receiver to produce 1% nitric oxide and 99%nitrous acid gas stream. The gas stream was bubbled through an optionalgas purifier, which contained a 1M sulfuric acid and 1M ferrous sulfatesolution by mixing 0.1 mole of sulfuric acid and 0.1 mole of ferroussulfate to 100 mL of water. The output of nitric oxide generated wasconstant in the therapeutic gas, for a period of several days. Thetherapeutic gas was substantially devoid of nitrogen dioxide.

EXAMPLE 5

[0033] Using an apparatus depicted in FIG. 1, a aqueous solution of 2grams of sodium nitrite, and pH buffer combination of 0.1 mole aceticacid and 0.1 mole sodium acetate was preprared in 100 mL of water. Thesolution was added to a non-electrolytic nitric oxide precursor receiverand the mixture was stirred. A diaphragm pump equipped with a restrictorvalve established a flow rate of 2 liters per minute of ambient air at20° C. The transport gas swept the headspace of the nitric oxidereceiver to generate the therapeutic gas. The output of nitric oxidegenerated was 50 ppm in the therapeutic gas, which remained constant at50 ppm+/−20 for five hours.

EXAMPLE 6

[0034] Using the apparatus depicted in FIG. 1, a pump equipped with arestrictor valve was used to supply 20° C. ambient air at a flow rate of2 L/min. Sodium nitrite (15 g) was added to the receiver containing 100mL of an aqueous solution of a buffer including 28 g of sodium hydrogenphosphate and 40 g of sodium phosphate monobasic. The solution wasstirred at room temperature (18-22° C.). The transport gas, air, wasswept over the headspace of the receiver into a gas purifier containingnitric oxide releasing agent 100 mL of 1 molar iron (II) sulfate (FeSO₄)and 4 mL of H₂SO₄ to remove impurities.

EXAMPLE 7

[0035] Using the apparatus depicted in FIG. 1, a pump was equipped witha restrictor valve to supply 20° C. ambient air at a flow rate of 2L/min. An aqueous solution (100 mL) was prepared of 15 g of the nitricoxide precursor sodium nitrite and a buffer consisting of 28 g of sodiumphosphate (Na₂HPO₄) and 40 g of sodium phosphate monobasic (NaH₂PO₄) wasplaced in the receiver. The reaction was stirred at room temperature(18-22° C.). The transport gas, air was swept over the headspace of thereceiver into a gas purifier containing nitric oxide releasing agent asshown in Table 1. TABLE 1 Experiment Nitric oxide releasing agentExperiment 1 100 mL water, 5 g NaI, 2 mL H₂SO₄ Experiment 2 100 mLwater + 5 g NaI + 2 mL H₂PO₄ Experiment 3 100 mL PotassiumBiphthalate/hydrochloric acid pH 3 buffer + 5 g NaI Experiment 4 100 mL1 M NaH₂PO₄ + 5 g NaI.

[0036] Other embodiments are within the scope of the following claims.

What is claimed is:
 1. An apparatus for delivering a therapeutic gasincluding nitric oxide comprising: a receptacle including a therapeuticgas outlet and a non-electrolytic nitric oxide precursor receiver; and atransport gas inlet fluidly communicating from a source of a transportgas to the therapeutic gas outlet through the non-electrolytic nitricoxide precursor receiver.
 2. The apparatus of claim 1 wherein thetransport gas inlet includes a gas distributor in the non-electrolyticnitric oxide precursor receiver.
 3. The apparatus of claim 1 furtherincluding a therapeutic gas delivery system fluidly connectable to thetherapeutic gas outlet.
 4. The apparatus of claim 3 wherein thetherapeutic gas delivery system includes a therapeutic gas purifier. 5.The apparatus of claim 4 wherein the therapeutic gas purifier includes afilter.
 6. The apparatus of claim 3 wherein the therapeutic gas deliverysystem includes a mask fluidly connectable to the therapeutic gasoutlet.
 7. The apparatus of claim 1 wherein the mask is connectable to amammal.
 8. The apparatus of claim 1 wherein the source of the transportgas includes a gas flow controller.
 9. A method of delivering nitricoxide to a mammal comprising: non-electrolytically generating atherapeutic gas from a nitric oxide precursor, wherein the therapeuticgas includes nitric oxide and is substantially devoid of nitrogendioxide; and transporting the therapeutic gas to a mammal.
 10. Themethod of claim 9 wherein non-electrolytically generating thetherapeutic gas includes contacting the nitric oxide precursor with abuffer solution to form a mixture.
 11. The method of 10 wherein thebuffer solution includes a pH buffer combination selected from a groupconsisting of acetic acid/acetate, hydrochloric acid/chloride,hydrochloric acid/citrate, citric acid-phosphate, phosphoricacid/phosphate and citric acid/citrate.
 12. The method of 10 wherein thebuffer solution maintains a pH of the mixture in the range of 4 to 7.13. The method of 10 wherein the buffer solution maintains a pH of themixture in the range of 6.5-6.9.
 14. The method of 9 whereintransporting the therapeutic gas includes contacting the transport gaswith the mixture..
 15. The method of claim 9 wherein transporting thetherapeutic gas includes delivering at least 1 ppm nitric oxide to themammal.
 16. The method of claim 9 wherein transporting the therapeuticgas includes delivering less than 100 ppm of nitric oxide to the mammal.17. The method of claim 9 wherein the therapeutic gas contains 20 to 60ppm of nitric oxide.
 18. The method of claim 9 further comprisingcontrolling a flow rate of a transport gas through the precursor in therange of 1 to 20 liters per minute.
 19. The method of claim 9 furthercomprising controlling a flow rate of the transport gas is in the rangeof 1 to 5 liters per minute.
 20. The method of claim 9 wherein thetransport gas includes oxygen.
 21. The method of claim 9 wherein thetransport gas includes ambient air.
 22. The method of claim 9 whereinthe transport gas includes an air and oxygen mixture.
 23. The method ofclaim 9 further comprising passing the therapeutic gas through a gaspurifier prior to transporting the gas.
 24. The method of claim 23wherein the gas purifier includes a pyrolizer, a reduction oxidationagent, or a semi-permeable membrane.
 25. The method of claim 9 whereinthe nitric oxide precursor includes a precursor salt.
 26. The method ofclaim 25 wherein the precursor salt includes a nitrite salt.
 27. Themethod of claim 9 wherein the nitric oxide precursor includes a nitritesalt selected from a group consisting of potassium nitrite, sodiumnitrite, rubidium nitrite, strontium nitrite, barium nitrite, calciumnitrite, copper nitrite and zinc nitrite.
 28. The method of claim 26wherein the nitrite salt includes sodium nitrite.
 29. The method ofclaim 9 wherein generating the therapeutic gas includes releasing nitricoxide from the precursor for over at least one hour.
 30. The method ofclaim 9 wherein generating the therapeutic gas includes releasing nitricoxide from the precursor over a period of time from one hour to sevendays.
 31. The method of claim 9 wherein generating the therapeutic gasincludes releasing nitric oxide from the precursor over a period of timefrom two hours to 24 hours.
 32. The method of claim 23 wherein the gaspurifier includes a ferrous salt.
 33. The method of claim 9 wherein thetherapeutic gas is substantially devoid of nitrogen dioxide.
 34. Themethod of claim 9 wherein generating the therapeutic gas includescontacting the nitric oxide precursor with a nitric oxide releasingsalt.
 35. The method of claim 34 wherein the nitric oxide releasing saltincludes a ferrous salt.
 36. A kit comprising a nitric oxide precursorand instructional material describing a method of generating atherapeutic gas and transporting the therapeutic gas, the therapeuticgas comprising nitric oxide and being substantially devoid of nitrogendioxide.
 37. The kit of claim 36 wherein the nitric oxide precursorincludes a precursor salt.
 38. The kit of claim 37 wherein the precursorsalt includes a nitrite salt.
 39. The kit of claim 36 wherein the nitricoxide precursor includes a nitrite salt selected from a group consistingof potassium nitrite, sodium nitrite, rubidium nitrite, strontiumnitrite, barium nitrite, calcium nitrite, copper nitrite and zincnitrite.
 40. The kit of claim 39 wherein the nitrite salt includessodium nitrite.
 41. The kit of claim 36 wherein generating thetherapeutic gas includes releasing nitric oxide from the precursor overa period of time from one hour to seven days.
 42. The kit of claim 41wherein generating the therapeutic gas includes releasing nitric oxidefrom the precursor over a period of time from two hours to 24 hours.